Implants with modified surfaces for increased biocompatibility, and method for production thereof

ABSTRACT

An implant with a surface modified for improved bio-compatiability consisting of a metal or an alloy thereof, said implant surface comprising a modified outer layer is disclosed, wherein said metal preferably is titanium, zirconium, hafnium or tantalum, and most preferably titanium, and said modified outer layer preferably comprises a hydride of said metal. Also a method for the production of such an implant is disclosed.

This application is the national phase under 35 U.S.C. §371 of PCTInternational Application No. PCT/IB99/02093 which has an Internationalfiling date of Dec. 22, 1999, which designated the United States ofAmerica and was published in English.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a biocompatible implant consistingessentially of a metal such as titanium, zirconium, hafnium andtantalum, or an alloy thereof, the surface of which has been modified inorder to increase ,the biocompatibility. The invention also relates to amethod modification of surfaces to.

BACKGROUND OF THE INVENTION

Titanium, zirconium, hafnium and tantalum and their alloys have a superbcorrosion resistance in body fluids and are well accepted by the humanbody. Titanium and its alloys are therefore much used for implants. Inmany applications it is of utmost importance that the metal form astrong and lasting connection with the surrounding tissues and that thisconnection does not impair healing. This is not easy to achieve. Implantmaterials not giving satisfactory healing usually lead to loss ofcontact between the implant and tissue, often followed by complicationsleading to implant failure. This has given the patients severe pain andrequired costly medical treatment often including complicated andexpensive surgery.

To deal with these problems geometric modifications of implants havebeen applied. Increasing the surface roughness expands the area oftissue contact. Different methods including plasma spraying, sandblasting or creation of holes or grooves to establish an inter-lockingeffect in the bone have achieved this. Electron beam machining has beenused to make surfaces that hardly can be produced with conventionalmachining. These latter methods can be optimised to also give additionalgeometrical advantages. Another method commonly used is to apply a layerof hydroxyapatite coating onto the titanium implant surface. Thismineral is present in hard tissue of all mammals. All these techniquesare manufacturing- and user- sensitive and it is problematic to carryout coating in a way that gives sufficient bonding between the mineraland the metal. Another serious disadvantage with these techniques isdestruction of the mineral coating during applications where stress isapplied to the implant. This seriously hampers applications of metalimplants.

In contact with oxygen titanium, zirconium, hafnium and tantalum andtheir alloys are instantaneously covered with a thin layer of oxide.Various techniques exist to increase the thickness of the oxide layer.Significant improvements have not been obtained so far, concerning thebiocompatibility of the implant material. The oxide layer may be furthertreated. For example EP-A-0 264 354 describes a process for forming acoating of a calcium phosphate compound on the surface of the titaniumoxide layer. In the process to obtain the desired oxide layer it ispossible to use either acid treatment or formation of an intermediatemetal hydride, which is then heated in order to obtain the desired oxideas a substrate for the calcium phosphate coating.

Another method for treating the surface of endosseous implants is to usethe process described in EP-A-0 212 929, according to which a ceramicmaterial is thermally sprayed onto the metal surface after its beenroughened with an appropriate technique. The roughening of the metalsurface may be obtained by e.g. thermally spraying titanium hydride ontoit, but, as for EP-A-0 264 354, the titanium hydride coated implant isonly an intermediate product in the process of obtaining the desired endproduct, in this case the ceramic coated implant.

SUMMARY OF THE INVENTION

The object of the present invention is to provide an implant withimproved biocompatibility compared to known implants. This is obtainedby modifying the surface of the implant. The modified surface furtherpromotes contact between tissue ant implant. In the research workleading to the present invention it was surprisingly observed thatimplants coated with titanium hydride led to a better adherence betweenthe metal and bone, compared to other titanium implants. The fact thattitanium hydride coated implants could be used directly is verysurprising; up to the present invention it has been considered necessaryto coat hydrided surfaces to achieve satisfactory biocompatibility. Inthe work leading to the present invention it was demonstrated in animalmodels that tissues in contact with the titanium hydrided titaniumsurface was healthy and showed no foreign body reactions as examined bymicroscopy.

The present invention thus relates to biocompatible metallic implants,characterized in that the surfaces of the implants have been modified sothat they comprise a metal hydride layer.

The invention also relates to a method for the production of abiocompatible implant, wherein a core of metal or an alloy thereof iscoated with a surface layer of hydride.

The characterizing features of the invention will be evident from thefollowing description and the appended claims.

DETAILED DESCRIPTION OF THE INVENTION

As stated above, the invention relates to a biocompatible implantconsisting essentially of metal or an alloy thereof, characterized inthat the surface of the implant is modified, preferably so that itcomprises an outer layer, preferably essentially consisting of a metalhydride. The expression “biocompatible implant” used herein relates toimplants suitable for introduction into the body of a mammal, andespecially of a human. The implants according to the invention orimplants produced with the method according to the invention areintended for introduction into all living hard and soft tissues,including bone, cartilage and teeth, and all body cavities includingjoints and inner ear.

The hydride layer in the implant according to the invention may be anymetal hydride or a mixture of several different metal hydrides.

In the case of an implant of titanium or an alloy thereof the major partof the modified outer layer, i.e. more than 50%, is preferablyconstituted by TiH_(1.924) or TiH₂. This titanium hydride layer may alsocomprise small amounts of other elements and hydrides thereof.

The invention also relates to a method suitable for the production ofthe above described biological implant. This method results in animplant surface, which comprises a layer of hydride. This may beperformed either by coating with a layer of hydride, or by convertingthe surface into hydride. It is possible to use a commercially availableimplant and convert its surface to comprise a hydrided layer. It is alsopossible to produce the implant according to the invention, by firstproducing a suitably shaped core of titanium or an alloy thereof, andthen accomplish the titanium hydride layer.

The method according to the invention is preferably performed bytreating the starting implant or core by electrolysis. The startingimplant is then placed in an electrolytic bath. During the electrolysis,the starting implant will constitute the cathode.

The electrolytic bath is preferably an aqueous solution of NaCl withacidic pH-value. The pH is preferably adjusted to the appropriate valueby addition of HCl, H₂SO₄, HNO₃, HClO₄ , or an organic acid or a mixtureof two or more of these acids.

The temperature of the electrolytic bath should also be adjusted. It ispossible to perform the method according to the invention at ambienttemperature, i.e. at approximately 20° C., however, at this temperaturethe reaction rate will be very slow. In order to increase the reactionrate, the temperature should be raised, preferably to at least 40° C.,and most preferably to at least 80° C.

The most preferred electrolytic solution for use in the method accordingto the invention is an aqueous solution comprising from 0,01 M to 1 M ofa saturated salt solution and from 10⁻⁵ to 10 M of at least on of theabove mentioned acids.

The current used to perform the electrolysis is 0.001-1000 mA/cm².

In order to further improve the biocompatability of the implant it is tobe implanted into, it is advantageous to increase the surface roughnessof the hydride layer. This can for example be done by blasting, e.g.grit blasting, before hydriding the implant.

The invention will now be further explained in the following examples.These examples are only intended to illustrate the invention and shouldin no way be considered to limit the scope of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

In the examples below reference is made to the accompanying drawings onwhich:

FIG. 1 illustrates the thickness of titanium hydride layers obtained byelectrolysis of titanium implants at different temperatures andpH-values (see Example 1); and

FIG. 2 illustrates the forces necessary to pull out implants accordingto the invention compared to control implants, from the tibia of rabbits(see Example 4).

EXAMPLES Example 1

Specimens of Titanium Grade 2 were carefully cleaned by ultrasonictreatment with trichlorethylene for 15 min, rinsed in ethanol, and thenultrasonic treated with ethanol for 10 min. This was repeated threetimes, and the specimens were then rinsed in water. The clean specimenswere then cathodically polarized in a bath consisting of 0.5 M NaCl and1 M HCl. The presence of a titanium hydride after the electrolysis wasconfirmed by X-ray diffraction analysis.

The electrolysis was performed at different temperatures, 25° C. and 80°C., in order to study the influence of the temperature on the obtainedtitanium hydride layer, and also at different pH-values, pH 0 and pH 2,in order to study the influence of the pH.

The thickness of the obtained titanium hydride layer was determined bymicroscopy of metallographic cross sections. The thickness as a functionof the time used for the treatment is shown in FIG. 1.

As evident from the figure, it is preferable to use a temperature of 80°C. compared to a temperature of 25° C.

Example 2

Experimentally produced implants were made of titanium grade 2. Theimplants were threaded and had a diameter of 3.5 mm and a length of 4.5mm. The implants were made to fit the bones of rabbits. The implantswere treated for 18 hours in the same bath and under the same conditionsas used in example 1. After sterilization by autoclaving, these implants(Implants of the invention) were introduced by surgery in the femurs offour rabbits. These rabbits were reproduced with special care to renderanimals with very similar genetics.

For comparison, implants that were only cleaned and autoclaved(Reference implants) were introduced in similar positions in therabbits.

Three implants with titanium hydride layers and two with cleaned andautoclaved surface were present in each rabbit. The rabbits wereeuthanized after 8 weeks. The adherence between the implants and thebone was recorded for eight implants with titanium hydride coating andfour implants that had only been cleaned and autoclaved. The adherencewas determined by measuring the torque force (Ncm) needed to loosen theimplants from the femur of the rabbits. The results are shown in table 1below.

TABLE 1 Removal torque (Ncm) ± SD Mean Implants 45.1 52.5 36.2 53.5 83.259.1 87.6 68.2 18.0 60.7 of the invention Reference 10.2 12.3 14 17.5 —— — — 3.1 13.5 implants

From the table, it is evident that the implants with a surface layer oftitanium hydride had a much better adherence than those without.Histology showed normal cells in contact with titanium hydride.

Example 3

Strength and stability of interface between metal and bone is criticalto the long-term performance of load bearing implants in particular bonewith poor quality. Data has been presented that rough surfaces inducebetter bone response, however the ideal type and degree of roughnessremains unknown.

In this example the bone response to titanium with different surfaceroughness expressed by bone to implant retention was investigate. A testmodel was developed using coin shaped commercial pure (c.p.) titaniumimplants. With this model, further described below, the effect of thefrictional forces during pull-out test is minimised. Different surfacestructures were obtained by grit-blasting with TiO₂, using differentgrain sizes.

The implants had the shape of disks, and they were machined from a 10 mmround bar of grad 2 titanium (ASTM B 348). The size of the disks was6,25±0,01 mm in diameter with a thickness of 2.0±0,05 mm.

All disks were standardised with grinding disc from #800 to #1200 gritsize and polished with 6μ diamond abrasive, according to Struers®Metalog Guide before further treatments.

All disks were pre-treated with trichloroethylene in an ultrasonic bathfor 30 min, rinsed with ethanol then ethanol in ultrasonic bath for3×10-min, and finally rinsed with deionized water.

A total of forty-eight implants were divided into three groups: Group 1:implants with electropolished surfaces, Group 2: implants that wereblasted with TiO₂ particles with a grain size of 22-28 μm, and Group 3:implants that were blasted with TiO₂ particles with a grain size of180-220 μm. Eight implants in each group were used as controls, whilethe other eight in each group were treated according to the invention.Four implants, one from each group were randomly in-operated into thetibial bone of each of the twelve New Zealand White rabbits. Beforesurgery, the rabbits were given Fentanyl/fluanison (Hypnorm®) 0,05-0,1ml/kg s.c. 10 minutes prior to being removed from their cages. Theoperation sites were depilated and washed with soap and ethanol prior toa sterile cover of the lover part of the rabbit. The rabbits wereanaesthetised with Midazolam (Dormicum®) 2 mg/kg bw i.v. If the animalsstarted to show signs of waking up between 0,1 to 0,5 diluted Hypnorm®(1 ml Hypnorm® and 9 ml sterile water) was injected i.v. slowly until anadequate effect was obtained. Local-anaesthesia, Lidocain(Xylocain/adrenaline®) 1,8 ml s.p. in joint site, tuberositas tibiae,was used. The animals were placed on the operation table on their back,covered with sterile cloths prior to disinfection with 70% etanol. Theireyes were protected for drying with ointment.

Two implants were placed in each proximal tibia. An incision of 5 cm wasmade on the medial-anterior part of tibiae, starting approximately 2 cmfrom patella. The incision penetrated epidermis, dermis and the faciallayers. Lateral reflection of these tissues exposed the underlyingperiosteum. Additional medial-anterior incision was made through theperiosteum. A 1,0-mm diameter twist drill (Medicon®) in a handle wasused to get two guide holes with 8 mm distance. A 6,65 mm diameterstainless steel bur in a slow-speed handpiece with physiological salinesolution irrigation was used to get flat cortical surfaces for theimplants and the individually fitted Teflon caps, which were used tocover the implants to prevent bone overgrowth. Care was taken to preventbreaching the cortical bone. Two implants were placed on the evenprepared surface of the cortical bone. To stabilise the implants atitanium-plate (Medicon® CMS) in proximal-distal direction, wereretained with two titanium screws. The facial layers were repositionedand sutured with 4-0 polyglycolic acid suture. The superficial layerswere sutured using an intra cutanos technique with the same 4-0 suture.

After surgery, each animal received an injection with 20 ml NaClinfusion s.c. and 0,05 mg Temgesic® “Reckitt & Colman” 0,02-0,05 mg/kgs.c.

As post op analgesic the animals received 0,05 mg Temgesic® for fourdays.

Observation time was set for 8 weeks. The fixation of the implants tobone was then evaluated using a pull-out test. The rabbits weresacrificed with an over-dose i.v. and an intracardiac injection withPentobarbital (Mebumal®) while under sedation with Hypnorm®.

Immediately after euthanisation the superficial tissues overlying theimplants were removed to expose the Teflon caps. The titanium plate wascarefully removed and the Teflon cap separated from the implants usingpressure-air. Tibia was cut in the knee joint and fixated in a specialdesigned jig, which was anchored to the bed of the testing machine tostabilise the bone during the pull-out procedure. A metal pin with a“ball” in one end and threads in the other was fastened in pre-threadsimplants.

The equipment used to apply pull-out force was Lloyds LRX MaterialsTesting machine. The ball-attachment on the metal pin was fit in aholder connected to a load cell of 500 N. This attachment was designedto avoid any shear and tilt forces on the implant and tolerates for theaxis of the implant not being precisely perpendicular on the bonesurface. Crosshead speed range was set to 1,0 mm/min. Force measuringaccuracy was set to +/−1%.

The results of the pull-out test are shown in FIG. 2.

It is evident that the implants according to the invention, i.e. theimplants with hydrided surfaces, showed a better bone fixation than thecontrols.

What is claimed is:
 1. A sterile implant with a surface modified forimproved biocompatibility and consisting of a metal or an alloy thereof,characterized in that the surface of the sterile implant comprises ahydrided outer layer.
 2. An implant according to claim 1, wherein saidmetal is titanium, zirconium, hafnium or tantalum.
 3. An implantaccording to claim 2, wherein said modified outer layer consists of ahydride of titanium, zirconium, hafnium or tantalum.
 4. An implantaccording to claim 3, wherein said metal is titanium.
 5. An implantaccording to claim 4, wherein said hydrided outer layer consists of atitanium hydride.
 6. An implant according to claim 1, wherein theimplant surface comprises a geometrical modification of the outer layer.7. A biocompatible implant according to claim 1 intended for implantinginto living organisms.
 8. A biocompatible implant according to claim 7intended for replacement of lost or damaged body parts.
 9. Abiocompatible implant according to claim 7 intended for restoringfunction of lost or damaged body parts.
 10. A biocompatible implantaccording to claim 7, wherein said implant is a dental implant.
 11. Abiocompatible implant according to claim 7, wherein said implant is anorthopedic implant.
 12. A method for the production of a biologicalimplant according to claim 1, wherein a core of a metal or an alloythereof is coated with a surface layer of a metal hydride, and thecoated core is sterilised.
 13. A method according to claim 12, whereinsaid metal is titanium, zirconium, hafnium or tantalum.
 14. A methodaccording to claim 13, wherein said metal hydride is a hydride oftitanium, zirconium, hafnium or tantalum.
 15. A method according toclaim 12, wherein said metal is titanium.
 16. A method according toclaim 15, wherein said metal hydride is a titanium hydride.
 17. A methodaccording to claim 12, wherein said core of a metal is a startingimplant of titanium or an alloy thereof.
 18. A method according to claim12, wherein said core of a metal is treated by electrolysis therebyconverting the surface region one or more hydrides of the metal or alloythereof constituting the core.
 19. A method according to claim 18,wherein said core of a metal, constituting a cathode, is placed in anelectrolytic bath.
 20. A method according to claim 19, wherein said bathis an acid aqueous solution of NaCl.
 21. A method according to claim 20,wherein said bath has a pH-value below 4 and a temperature of at least40° C.
 22. A method according to claim 21, wherein the temperature ofthe bath is at least 80° C.
 23. A method according to claim 19, whereinthe pH-value of the bath is adjusted by addition of at least one acidselected from the group consisting of HCl, H₂SO₄, HNO₃ and HClO₄.
 24. Amethod according to claim 23, wherein said bath is an aqueous solutioncomprising 0.05-1 M NaCl and 3·10⁻⁴-2 M of the acid.
 25. A methodaccording to claim 18, wherein the density of the current used toperform the electrolysis is 0.1-10 mA/cm².
 26. A method according toclaim 12, wherein the surface roughness of the titanium hydride layer isincreased.
 27. A method according to claim 26, wherein the surfaceroughness is increased by blasting the implant.
 28. A method accordingto claim 12, wherein the implant is etched in a bath consisting of anaqueous solution comprising fluorine ions in a concentration of 0.2-10M, said bath having a pH-value of 3.3-7.
 29. A method according to claim12, wherein the implant produced is intended for osseointegration.
 30. Amethod according to claim 12, wherein the implant produced is a dentalimplant.
 31. An implant which is implanted in biological tissue and indirect contact with said tissue, said implant consisting of a metal oran alloy thereof, wherein the surface of the implant comprises ahydrided outer layer to provide improved biocompatibility.
 32. Animplant according to claim 31, wherein said metal is titanium,zirconium, hafnium or tantalum.
 33. An implant according to claim 32,wherein said modified outer layer consists of a hydride of titanium,zirconium, hafnium or tantalum.
 34. An implant according to claim 32,wherein said metal is titanium and said hydrided outer layer consists ofa titanium hydride.
 35. An implant according to any one of claims 32-34,wherein the implant surface comprises a geometrical modification of theouter layer.
 36. An implant according to any one of claims 32-34,wherein said tissue is dental tissue.
 37. An implant according to anyone of claims 32-34, wherein said tissue is bone tissue.